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Kidney Week

Abstract: FR-PO591

Renal TNFα Activates WNK Phosphorylation Cascade and Contributes to Salt-Sensitive Hypertension in CKD

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Furusho, Taisuke, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
  • Mandai, Shintaro, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
  • Kikuchi, Hiroaki, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
  • Takahashi, Naohiro, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
  • Fujimaru, Takuya, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
  • Hashimoto, Hiroko, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
  • Arai, Yohei, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
  • Ando, Fumiaki, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
  • Mori, Takayasu, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
  • Susa, Koichiro, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
  • Isobe, Kiyoshi, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
  • Nomura, Naohiro, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
  • Okado, Tomokazu, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
  • Rai, Tatemitsu, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
  • Yamamoto, Kohei, Department of Comprehensive Pathology, Tokyo Medical and Dental University, Tokyo, Japan
  • Uchida, Shinichi, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
  • Sohara, Eisei, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
Background

The inappropriate over-activation of with-no-lysine kinase (WNK)–STE20/SPS1–related proline/alanine-rich kinase (SPAK)–NaCl cotransporter (NCC) phosphorylation cascade increases sodium reabsorption in distal kidney nephrons, resulting in salt-sensitive hypertension. Although chronic kidney disease (CKD) is a common cause of salt-sensitive hypertension, the involvement of WNK phosphorylation cascade is unknown. Moreover, the effect of immune systems on WNK kinases has not been investigated despite the fact that immune systems are important for salt sensitivity.

Methods

WNK phosphorylation cascade and its contribution to salt sensitivity was evaluated in three CKD mouse models (aristolochic acid nephropathy (AAN), adenine nephropathy and subtotal nephrectomy). The regulator of WNK signaling in CKD was also explored focusing on immune systems.

Results

Immunoblotting and immunofluorescent study revealed that the protein abundance of WNK1, but not of WNK4, was increased at the distal convoluted tubules (DCT) in the AAN kidney. Accordingly, the phosphorylation of SPAK and NCC was also increased. Moreover, a high-salt diet did not adequately suppress the activation of WNK1–SPAK–NCC phosphorylation cascade in AAN, leading to salt-sensitive hypertension. WNK1 also was increased in adenine nephropathy, but not in subtotal nephrectomy, models. By comparing the transcripts of these three models focusing on immune systems, we hypothesized that TNFα regulates WNK1 protein expression. In fact, TNFα increased WNK1 protein expression in cultured cells by reducing the transcription and protein levels of NEDD4-2 E3-ligase, which degrades WNK1 protein. Furthermore, the TNFα inhibitor etanercept reversed the reduction of NEDD4-2 expression and upregulation of WNK1–SPAK–NCC phosphorylation cascade at DCT in vivo in the AAN kidney.

Conclusion

TNFα activates WNK1–SPAK–NCC phosphorylation cascade in the kidney, leading to salt-sensitive hypertension in CKD. These observations provide the new mechanism how immune systems regulate salt-sensitivity in CKD.

Funding

  • Government Support - Non-U.S.